Pediatric Nephrology

https://doi.org/10.1007/s00467-018-4093-1

REVIEW

Treatment of steroid-resistant nephrotic syndrome in the genomic era

Adam R. Bensimhon 1 & Anna E. Williams 1 & Rasheed A. Gbadegesin 1,2,3

Received: 6 July 2018 / Revised: 13 September 2018 / Accepted: 18 September 2018

# IPNA 2018

Abstract
The pathogenesis of steroid-resistant nephrotic syndrome (SRNS) is not completely known. Recent advances in genomics have
elucidated some of the molecular mechanisms and pathophysiology of the disease. More than 50 monogenic causes of SRNS
have been identified; however, these genes are responsible for only a small fraction of SRNS in outbred populations. There are
currently no guidelines for genetic testing in SRNS, but evidence from the literature suggests that testing should be guided by the
genetic architecture of the disease in the population. Notably, most genetic forms of SRNS do not respond to current immuno-
suppressive therapies; however, a small subset of patients with monogenic SRNS will achieve partial or complete remission with
specific immunomodulatory agents, presumably due to non-immunosuppressive effects of these agents. We suggest a pragmatic
approach to the therapy of genetic SRNS, as there is no evidence-based algorithm for the management of the disease.

Keywords Nephrotic syndrome . SRNS . Genetic SRNS . Treatment . Genetic SRNS

Introduction children, accounting for about 80% of cases, while the

Nephrotic syndrome (NS) is the most common glomerular
disorder in childhood, with an incidence that ranges from ap-
proximately 2 to 7/100,000 children per year and a global
prevalence of approximately 16/100,000 children [1, 2]. It is
diagnosed by a constellation of clinical signs and symptoms
that include massive proteinuria, hypoalbuminemia, edema,
and hyperlipidemia. Childhood nephrotic syndrome is classi-
fied based on initial response to a standardized corticosteroid
therapy into steroid-sensitive nephrotic syndrome (SSNS) or
steroid-resistant nephrotic syndrome (SRNS). Despite the lack
of a global consensus regarding the definition of steroid resis-
tance, most experts agree that SRNS constitutes the failure to
achieve remission after 4–6 weeks of daily corticosteroid ther-
apy [3, 4]. The SSNS variant is the most common among
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00467-018-4093-1) contains supplementary
material, which is available to authorized users.
* Rasheed A. Gbadegesin
rasheed.gbadegesin@duke.edu
1
Department of Pediatrics, Division of Nephrology, Duke University
Medical Center, Durham, NC 27710, USA
2
Department of Medicine, Division of Nephrology, Duke University
Medical Center, Durham, NC 27710, USA
3
Duke Molecular Physiology Institute, Durham, NC, USA
SRNS variant accounts for the remaining 20% of cases and
typically portends an unfavorable prognosis [5]. Most chil-
dren with SRNS will progress to end-stage kidney disease
(ESKD) within 5–10 years of diagnosis [6, 7].
The etiology of SRNS is unknown in the majority of chil-
dren with the disease; however, data from genomic studies in
the last 20 years suggest that most cases of SRNS are probably
due to structural and functional defects of the podocyte, the
glomerular visceral epithelial cell. Strikingly, the majority of
the over 50 single-gene causes of hereditary NS are critical for
the functional integrity of the podocyte; thus, most clinicians
now refer to SRNS as a podocytopathy [8].
The prevalence of genetic SRNS is unknown due to the
dearth of population-based studies. Reported prevalence
varies between 4 and 30%, with a higher prevalence among
inbred populations and a lower prevalence in heterogeneous
outbred populations [9–13]. Sadowski et al. [9] studied 1783
unrelated families and found the prevalence of monogenic NS
to be 29.5%; however, mutation prevalence varies widely be-
tween different regions of the world, with the highest preva-
lence in regions of the world where consanguinity is common.
In addition, there is currently no data from Africa on disease
burden due to monogenic NS. While genetic SRNS is being
increasingly recognized, there is no standardized approach to
the management of children with genetic NS. In addition, the
relationship between genetic mutations and response to ther-
apy has not been established, but it has been reported that the

prevalence of resistance to corticosteroid therapy and other
immunosuppressive agents is significantly higher in patients
with genetic NS compared to those with non-genetic disease
[14, 15], though there are isolated reports in the literature
describing patients with monogenic SRNS who have
responded to immunosuppressive therapies. To further com-
pound the dilemma of treatment decision in genetic NS, there
is accumulating evidence from pre-clinical studies that, in ad-
dition to their immunomodulating effects, the effects of im-
munosuppressive agents such as corticosteroids and calcine-
urin inhibitors in NS may be partially due to their stabilizing
effects on the podocyte F-actin cytoskeleton, suggesting that
these agents may be useful in the treatment of SRNS due to
structural defects of the podocyte [16–19].
In this review, we will address the indications for genetic
testing in SRNS and discuss the implications of a positive and
negative genetic test result on management decisions and
long-term prognosis. We will discuss the current evidence
available for making decisions on whether or not to use im-
munomodulatory therapy and/or other supportive agents in
the management of SRNS. We will also suggest a practical
approach to handling this clinical scenario in day-to-day
practice.
Etiology and pathogenesis of SRNS
SRNS is a clinically heterogeneous condition that is associat-
ed with different morphologic changes on kidney biopsy. The
most common pathologic variant associated with SRNS in
children is focal segmental glomerulosclerosis (FSGS).
FSGS is a pathologic finding that is characterized by focal
glomerulosclerosis or tuft collapse, segmental hyalinosis,
IgM deposits on immunofluorescence staining, and podocyte
foot process effacement [20, 21]. Clinically, FSGS is charac-
terized by rapid progression to ESKD within 5–10 years of
diagnosis [6, 7]. It is increasingly being recognized that mor-
phological changes in kidney biopsies of patients with FSGS
are heterogeneous, and that the different morphologic types
may be associated with different disease courses [22], though
the detailed description of these variants is beyond the scope
of this review. Other less common lesions that may cause
SRNS include minimal change disease (MCD) and membra-
nous and membranoproliferative glomerulopathy.
The molecular pathogenesis of FSGS and other SRNSs is
not fully understood; however, there is evidence that SRNS is
caused by defects in the glomerular filtration barrier (GFB), the
charge and size-selective barrier that is made up of specialized
fenestrated endothelial cells, the glomerular basement mem-
brane (GBM), and glomerular epithelial cells (podocytes).
Data emanating from studies of familial FSGS suggest that
the podocyte is the most important component of the GFB in
that majority of the more than 50 genes mutated in hereditary
Pediatr Nephrol
FSGS affect the structure and functions of the podocyte and its
slit diaphragm [8, 23, 24]. These observations have given rise
to the concept of FSGS being a podocytopathy. In addition to
structural defects of the podocyte, putative soluble circulating
factors resulting from immune dysregulation may also cause
podocyte injury in patients with SRNS. Furthermore, maladap-
tive changes such as obesity, and conditions that result in re-
duced nephron number (e.g., congenital or acquired solitary
kidney, or preterm birth), can cause and perpetuate podocyte
injury [25–33]. It should be noted that soluble urokinase-type
plasminogen activator receptor (suPAR), CD80, and other
molecules have been linked to the etiology and pathogenesis
of SRNS, pattern of therapy response, and risk of recurrence
following kidney transplantation. However, the genetic basis
of how these molecules modulate disease course in NS is un-
known, and this topic will be the subject of another review.
Genetic SRNS
Monogenic SRNS
Monogenic SRNS can be of autosomal recessive (AR), auto-
somal dominant (AD), X-linked, or mitochondrial inheritance
[34]. Typically, recessive inheritance is characterized by early
onset of disease presentation and high penetrance and is some-
times associated with extra-renal manifestations. In contrast,
dominant inheritance is associated with later onset of disease
presentation and incomplete penetrance. Monogenic causes of
SRNS are probably responsible for a small proportion of all
cases of SRNS; however, data from studies of this small frac-
tion of patients with SRNS has improved our understanding of
disease pathobiology. The landmark discovery of nephrin
(NPHS1) as the gene mutated in congenital nephrotic syn-
drome by Tryggvason and his colleagues [24] drew attention
to the vital role of genetic and molecular analyses in under-
standing the pathogenesis of SRNS.
With the completion of the sequencing of the human ge-
nome and rapid improvements in high-throughput sequencing
technology, the rate of discovery of genes causing monogenic
SRNS has increased dramatically. Mutations in approximately
50 genes are now known to cause SRNS [9, 35–40]; however,
these genes are responsible for less than 20% of all cases of
SRNS, suggesting that SRNS is genetically heterogeneous
and there are still many unidentified genetic causes of the
disease. The majority of SRNS genes are enriched in the
podocyte and the slit diaphragm, as well as other components
of the GFB. A list of genetic causes of SRNS and the locali-
zation of the genes in the GFB is shown in Table 1. Genes
mutated in SRNS are generally rare in the genus population;
however, data from different cohorts seems to suggest that
mutations in NPHS1, NPHS2, and PLCE1 are the most com-
mon cause of autosomal recessive SRNS, while mutations in
Pediatr Nephrol

Table 1 Genetic causes of

nephrotic syndrome Gene Protein Mode of inheritance

Slit diaphragm genes

NPHS1 Nephrin AR
NPHS2 Podocin AR
PLCE1 Phospholipase C epsilon 1 AR
CD2AP CD2-associated protein AD, AR
TRPC6 Transient receptor potential channel C6 AD
CRB2 Crumbs family member 2 AR
FAT1 FAT atypical cadherin AR
Transcription factors and nuclear genes
WT1 Wilms tumor protein 1 AD
LMX1B LIM homeobox transcription factor 1-beta AD
SMARCL1 SMARCA-like protein AR
NUP93 Nuclear pore complex protein 93 AR
NUP107 Nuclear pore complex protein 107 AR
NUP205 Nuclear pore complex protein 205 AR
XPO5 Exportin 5 AR
E2F3 E2F transcription factor AD
NXF5 Nuclear RNA export factor 5 X-linked recessive
PAX2 Paired box protein 2 AD
LMNA Lamin A and C AD
WDR73 WD repeat domain 73 AR
Cytoskeletal and membrane genes
ACTN4 Alpha-actinin 4 AD
INF2 Inverted formin 2 AD
MYO1E Myosin 1E AR
MAGI2 Membrane-associated guanylate kinase, AR
inverted 2
ANLN Anillin actin binding protein AD
PTPRO Protein tyrosine phosphatase RO AR
EMP2 Epithelial membrane protein 2 AR
CUBN Cubilin AR
PODXL Podocalyxin AD
ARHGAP24 Rho GTPase-activating protein 24 AD
ARHGDIA Rho GDP dissociation inhibitor alpha AR
DLC1 DLC1 Rho GTPase-activating protein AR
KANK 1/2/4 Kidney ankyrin repeat-containing protein AR
ITSN 1/2 Intersectin protein AR
SYNPO Synaptopodin AD
TNS2 Tensin-2 AR
Mitochondrial, lysosomal, metabolic, and cytosolic genes
COQ2 Coenzyme Q2 4-hyroxybenzoate AR
polyprenyl transferase
COQ6 Coenzyme Q6 monooxygenase AR
PDSS2 Prenyl-diphosphate synthase subunit 2 AR
ADCK4 AarF domain-containing kinase 4 AR
SCARB2 Scavenger receptor class B, member 2 AR
PMM2 Phosphomannomutase 2 AR
ALG1 Asparagine-linked glycosylation 1 AR
TTC21B Tetratricopeptide repeat protein 21B AR
CDK20 Cyclin-dependent kinase 20 AR
 Pediatr Nephrol

Table 1 (continued)
Gene Protein Mode of inheritance

CFH Complement factor H AR

DGKE Diacylglycerol kinase epsilon AR
SPGL1 Sphingosine-1-phosphate lyase 1 AR
Glomerular basement membrane genes
LAMB2 Laminin subunit beta-2 AR
ITGB4 Integrin beta 4 AR
ITGA3 Integrin alpha 3 AR
COL4A 3/4/5 Type IV collagen alpha 3, 4, 5 AR, AD, X-linked
Endosomal regulator genes
GAPVD1 GTPase-activating protein and VPS9 AR
domain 1
ANKFY1 Ankyrin repeat and FYVE domain AR
containing 1

AR autosomal recessive, AD autosomal dominant

INF2, COL4A3, COL4A4, WT1, TRPC6, ACTN4, and
LMX1B are responsible for most cases of autosomal dominant
SRNS [11, 40–50]. It should be noted that the prevalence of
mutations in these genes also varies widely between different
regions of the world; for example, R138Q and R138X muta-
tions in NPHS2 represent founder mutations in Central Europe
[51]. More recently, Winkler et al. reported that NPHS2
V260E may also represent a founder mutation among blacks
in South Africa (Cheryl Winkler, PhD, personal communica-
tion, 26 June 2018). Generally, patients with genetic SRNS
progress more rapidly to ESKD than those with non-genetic
disease [12]; however, the rate of disease recurrence post-
transplantation in those with genetic disease is much lower
than that in those with non-genetic disease. In some studies,
recurrence risk in genetic SRNS was reported as less than 8%
compared with 30% in patient populations with non-genetic
causes [12, 14, 15, 52].
Polygenic SRNS
A full discussion of the role of polygenic inheritance in SRNS
is beyond the scope of this review; however, it is worth noting
that two variants in APOL1 gene [G1 allele (rs73885319 or
rs60910145) and G2 allele (rs717853136)] were recently
identified as being responsible for excess risk of FSGS and
chronic kidney disease (CKD) in African Americans [53].
Heterozygosity for either of these alleles protects against
sleeping sickness, thereby conferring a survival advantage
similar to protection provided by sickle cell trait (hemoglobin
AS) against malaria. However, when the G1 and G2 alleles are
inherited in a homozygous or a compound heterozygous man-
ner, these alleles confer a 7- to 17-fold increased odds for
FSGS and a plethora of other forms of CKD in African
Americans [53, 54]. In addition, variants in glypican-5
(GPC5) were reported to be associated with FSGS and
MCD in Japanese adults [55]. It should be noted that variants
in polygenic genes are not causal and they will result in dis-
ease only in the presence of additional modifier variants and
environmental factors. For example, only about 25% of indi-
viduals with the high-risk APOL1 genotype will develop CKD
in their lifetime.
The role of genetic testing in SRNS
Genetic testing in clinical practice is emerging as an invalu-
able diagnostic and prognostic tool in the management of
children with SRNS. Mutation detection in patients with
SRNS potentially allows for (1) a pragmatic approach to the
use of different immunosuppressive agents and avoidance of
side effects [56], (2) selection of targeted therapies that may
induce remission and/or delay progression to ESKD [57], (3)
prediction of clinical course and post-transplant disease recur-
rence [58], and (4) genetic counseling and possible antenatal
screening [59]. In addition to these clinical benefits, the con-
tinued discovery of novel SRNS genes will further our under-
standing of the pathogenesis of SRNS, aid in the precise def-
inition of disease phenotype, and allow for a personalized
approach to therapy.
Genetic testing methods
With improvements in high-throughput sequencing technolo-
gy, genetic testing is now widely available and is being de-
ployed by clinicians in routine evaluation of children with
SRNS. The most common methods used in the clinical setting
are the sequencing of a panel of candidate genes using direct
sequencing (Sanger sequencing) and targeted sequencing of
candidates (TSC) using a next-generation sequencing platform.
The latter approach is generally more practical, less laborious,
Pediatr Nephrol
and more cost-effective than direct sequencing, considering the
fact that there are over 50 genes known to cause SRNS, and the
number of causal mutations will likely continue to increase.
The advantages of the TSC approach include (1) high yield
of positive tests, especially in populations where mutation in
a particular gene or set of genes is known to be common; (2) the
ability to establish causality without extensive family studies;
and (3) the ability to more easily manage data from this ap-
proach compared with whole exome sequencing (WES) or
whole genome sequencing (WGS). The major limitation of
the TSC approach is that mutations in novel genes cannot be
identified, and a negative result does not necessarily rule out
genetic SRNS since the individual may have a mutation in a
yet-to-be-discovered novel gene.
The other approach that is less commonly used in clinical
practice is WES, where enrichment strategies are used to se-
quence only the protein-coding regions of the gene (exome),
which accounts for only 1% of the entire human genome, or
WGS, where both the coding and the non-coding regions are
sequenced. The advantages of WES and WGS are that they
are all inclusive and mutations may be detected in both can-
didate and novel genes, especially with the availability of
informative pedigrees. However, compared with TSC, WES
and WGS are more expensive, and they are more likely to
generate uninterpretable data especially when informative
pedigrees are not available. In addition, this approach may
identify potential pathogenic variants that are irrelevant to
SRNS but have potential consequences on the health and
well-being of the patients.
Indications for genetic testing
While various genetic testing modalities are now widely avail-
able, there are no guidelines for when or on whom genetic
testing should be done. However, if we view genetic testing
like any other diagnostic test, clinicians should consider
whether the test result is apt to alter the management of the
patient or better inform discussion of disease prognosis and
genetic counseling [34]. If testing will provide any of this
information, genetic testing is probably indicated.
Based on the variable prevalence of genetic SRNS in dif-
ferent populations, the approach to genetic testing will depend
on where the clinician is practicing. For example, in regions of
the world where inbreeding is highly prevalent or in popula-
tions where there is high prevalence of a particular founder
mutation, one can make a case for routine genetic testing for
all children with SRNS by sequential TSC followed by WES
or WGS if no mutation is detected (Fig. 1a). On the other
hand, in an outbred population where the likelihood of a pos-
itive test is low, genetic testing may be limited to children with
onset of disease in infancy, family history of SRNS or CKD,
and syndromic SRNS (Fig. 1b) [9, 13, 34]. A strong point in
support of the latter approach is a recent finding from our
group that mutation detection rate in patients with a family
history of SRNS and/or CKD is about 40% compared with a
6% rate of detection in those without a family history of CKD
(Varner et al., manuscript in preparation).
Approaches to management of SRNS
Specific therapy
Corticosteroids
The initial treatment for all children presenting with NS gener-
ally includes daily corticosteroid therapy for 6 weeks followed
by alternate-day therapy for another 6 weeks, for a total of
3 months of treatment [4]. Steroid resistance is defined as a
failure to achieve remission following 6 weeks of daily therapy.
It should be noted that more than 90% of children who are
steroid-sensitive will achieve remission within 4 weeks of ther-
apy initiation [60]. In contrast, adult literature seems to suggest
that longer duration of therapy may be needed before classify-
ing an adult as being steroid-resistant [61–64]. The mecha-
nisms of action of corticosteroids in NS are not fully elucidated;
however, the premise for their use is based on the evidence that
NS is an immunological disease and corticosteroids act by
suppressing T lymphocyte-mediated responses [25]. In addi-
tion to immunomodulatory effects, there are pre-clinical data
to suggest that corticosteroids may have non-immunologic ef-
fects on the F-actin cytoskeleton of the podocyte [17]. In a
study to determine the effects of glucocorticoids on podocytes,
Xing et al. [65] showed that dexamethasone upregulates the
expression of nephrin and tubulin-α in cultured human and
murine podocytes, suggesting a direct effect of glucocorticoids
on the podocyte actin cytoskeleton and regulation of critical slit
diaphragm proteins. More recently, Zhao et al. [18] demonstrat-
ed that α-actinin 4 (ACTN4) interacts with the glucocorticoid
receptor (GR) in the nucleus of human podocytes.
Glucocorticoids have also been shown to protect and enhance
recovery of cultured podocytes from puromycin
aminonucleoside (PAN)-induced injuries via actin filament sta-
bilization and protection from apoptosis [66, 67]. Recently,
Mallipattu et al. [68] demonstrated that in vitro treatment with
dexamethasone induced a rapid increase in Krüppel-like factor
15 (KLF15) expression in human and murine podocytes.
KLF15 is a kidney-enriched zinc finger transcription factor that
has been shown to be required for restoring podocyte differen-
tiation markers in cultured murine and human podocytes sub-
jected to stress [69]. Overall, these data suggest that in addition
to the effects of corticosteroids on T cell function, they may also
have direct effects on the podocyte cytoskeleton and slit dia-
phragm, indicating that corticosteroids may be useful in the
treatment of some forms of genetic NS. There are few reports
in the literature describing children with monogenic NS who

Fig. 1 Approach to genetic testing in SRNS. a Approach to genetic testing in population with high prevalence of SRNS such as an inbred population or
populations with founder mutations. b Approach to genetic testing in an outbred population
have achieved complete or partial remission following cortico-
steroid therapy (Supplementary Table 1) [70–72]. Based on
published data, there is currently no justification for extended
corticosteroid therapy in children with genetic SRNS.
Second-line immunomodulatory agents
In patients with SRNS, most clinicians will elect to use
second-line non-glucocorticoid agents to induce complete or
partial remission, as induction of even partial remission can
delay disease progression. Commonly used agents include
calcineurin inhibitors (CNIs), anti-proliferative agents such
as mycophenolate mofetil (MMF), and biologics like anti-
CD20 (rituximab). A brief description of the mechanism of
action of these agents and the rationale for their use in SRNS is
provided below.
Calcineurin inhibitors The two CNIs routinely used to treat NS
are cyclosporine A (CsA) and tacrolimus (also known as
FK506). The immunosuppressive properties of CsA and ta-
crolimus result from inhibition of calcineurin, a calcium- and
calmodulin-dependent phosphatase [73, 74]. Both agents in-
hibit calcineurin, CsA by binding to cyclophilin, and FK506
by binding to protein 12 to form the FKBP12 complex, which
ultimately inhibits calcineurin [73, 74]. Inhibition of calcine-
urin results in suppression of the transcription of interleukin-2
and subsequent T cell activation [75, 76]. A number of ran-
domized clinical trials have suggested improved remission
rates following CNI therapy in patients with SRNS. The most
Pediatr Nephrol
comprehensive study to date is the National Institutes of
Health (NIH)-sponsored multicenter randomized trial of 192
children and young adults with steroid-resistant FSGS who
received either CsA or a combination of MMF and pulse
dexamethasone. In this study, 65% of patients in the CsA
arm achieved remission compared with 42% of those in
MMF/dexamethasone arm. Though the difference in remis-
sion was not significant, this study demonstrated that both
treatments are useful in the management of children with
SRNS [77]. In addition to immunosuppressive effects, the
anti-proteinuric effects of CNIs may also be mediated by
intra-renal hemodynamic changes and also by inhibition of
calcineurin-mediated degradation of synaptopodin and stabi-
lization of the podocyte actin cytoskeleton [17]. In another
study, CNIs were shown to stabilize the podocyte actin cyto-
skeleton by upregulation of cofilin-1 expression [78]. These
studies suggest that, like glucocorticoids, the non-
immunomodulatory effects of CNIs may also ameliorate the
clinical manifestations of genetic SRNS that are due to struc-
tural defects of podocytes and other components of the GFB.
Despite these potential effects on the GFB, a small case series
from the literature seemed to suggest that the majority of chil-
dren with genetic SRNS will not respond to CNI-based ther-
apy [56, 79, 80]. In a study of 91 children with SRNS, Buscher
et al. [79] reported that 55% of children with non-genetic
SRNS achieved complete remission and 13% were in partial
remission following treatment with CNIs compared with 0%
complete remission and 29% partial remission in children with
genetic SRNS who presented after the age of 3 months. A
Pediatr Nephrol
similar pattern has been reported in other studies [14, 15, 56,
70, 81–86]. A summary of studies reporting on the use of
CNIs and other therapeutic agents in children with genetic
SRNS can be found in Supplementary Table 1. The major
challenge in the use of CNIs and other second-line agents in
the treatment of children with genetic SRNS is that there are
no clinical or genetic predictors of response to therapy, nor is
there a guideline on when to stop therapy in unresponsive
patients.
Mycophenolate mofetil MMF is an anti-proliferative agent
that is used extensively for immunosuppression in solid organ
transplantation and has also been increasingly used for treat-
ment of SRNS [15, 87, 88]. MMF acts through its active me-
tabolite mycophenolic acid (MPA) as a non-competitive inhib-
itor of the enzyme inosine monophosphate dehydrogenase
(IMPDH), which preferentially inhibits B and T lymphocyte
proliferation. Its mechanism of action in the treatment of glo-
merular disease is not fully understood, but it has been shown
in both human and experimental studies that MMF may act by
suppressing lymphocyte proliferation and antibody produc-
tion. MMF also decreases interleukin-2, interleukin-4, and ad-
hesion molecule expression in the kidney [89–92]. Limited
clinical data suggest that MMF may induce complete or partial
remission in steroid- and CsA-resistant FSGS without causing
the side effects of nephrotoxicity that are seen with CNIs [93,
94]. In the NIH trial described above, a combination of MMF
and dexamethasone was found to be as effective as CsA in the
treatment of SRNS [77]. To date, there are no reports in the
literature on the use of MMF in children with genetic SRNS.
Rituximab Rituximab is a genetically engineered chimeric
monoclonal antibody, containing murine variable regions and
a human IgG1 constant domain directed against the CD20 an-
tigen expressed on the surface of B lymphocytes [95]. There are
a few case series in the literature to show that rituximab may
induce partial and complete remission in some children with
SRNS [96–101]. The mechanisms of action of rituximab in
both SSNS and SRNS are unknown; however, it has been
shown that rituximab directly modulates and protects podocytes
from injury by preserving sphingomyelin phosphodiesterase
acid-like 3b (SMPDL-3b) expression, suggesting that rituximab
may modulate podocyte function independent of its immuno-
modulatory effects [102]. There are currently no reports to show
that rituximab may be useful in the treatment of genetic SRNS.
Agents targeting pathways that are dysregulated
by specific mutations
One of the promises of the genomic revolution is that identi-
fication of genetic causes and genetic risk factors for SRNS
will lead to a better understanding of disease pathogenesis,
identification of novel diagnostic tools, and the development
of targeted therapeutic agents. Despite the fact that multiple
genetic causes of NS have been identified, there is a signifi-
cant lag in the utilization of this information to identify
targeted therapies for NS [103]. There are multiple reasons
for this lag, including but not limited to a lack of high-
fidelity cell lines to study podocytes in culture [103]. The
mouse- and human-derived podocyte cell lines that are cur-
rently used for biochemical characterization of disease-
causing mutations have provided some insight into pathways
that are defective in patients with genetic NS; however, they
have some major limitations because they lack essential
podocyte characteristics that may be important to achieving
a full understanding of the mechanisms of podocyte injury
[103]. For example, these cell lines do not form slit diaphragm
cross-bridges in vitro, thereby limiting our understanding of
the structural and signaling alterations induced by disease-
causing mutations [103]. In addition, mouse models that are
often used to study these mutations in vivo do not accurately
recapitulate phenotypes seen in humans [103]. Furthermore,
pathway analyses are not automated, and they are often labo-
rious and frequently require investigators with different skill
sets to carry out. Despite these limitations, some of these dis-
coveries have led to identification of targeted therapies, novel
therapeutic targets, or existing agents that may be repurposed
for the treatment of SRNS.
Coenzyme Q10 supplementation
Coenzyme Q (CoQ) is a small lipophilic molecule that is
synthesized ubiquitously in the inner mitochondrial mem-
brane and is involved in many essential cellular processes,
especially in the mitochondria [104]. The molecule is com-
posed of a quinone group and a polyisoprenoid tail of variable
length, depending on the species [105]. In humans, CoQ with
10 isoprenoid subunits is found abundantly in the mitochon-
dria and is named coenzyme Q10 (CoQ10) or ubiquinone
[106]. Aside from being an essential component of the mito-
chondrial electron transport chain, CoQ10 is required for py-
rimidine nucleoside biosynthesis and is one of the most potent
lipophilic antioxidants [104, 107]. Biosynthesis of CoQ10 re-
quires at least 16 different genes (PDSS1, PDSS2, COQ2,
COQ3, COQ4, COQ5, COQ6, COQ7, COQ8A, COQ8B,
COQ9, COQ10A, COQ10B, FDX1L, FDXR, and
ALDH3A1) [108–110]. Mutations in some of these genes
cause primary CoQ deficiency, a severe but treatable, mito-
chondrial cytopathy [111]. In contrast to most mitochondrial
respiratory chain disorders, for which no effective treatment
exists, children with primary CoQ10 deficiency respond to oral
supplementation [112]. Mutations in COQ6 and COQ2 have
been reported to cause syndromic and isolated SRNS [57, 111,
113]. Since the products of these genes have been identified as
being important in the synthesis of CoQ10, there are reports on
the use of CoQ10 supplementation in the treatment of children

with SRNS due to mutation in these genes [114]. Montini et
al. [112] described two siblings with missense mutations in
COQ2, one of whom was already in ESKD at presentation and
the other sibling presented with NS and was treated with oral
CoQ10 supplementation. This individual achieved partial re-
mission and has stable renal function after 5 years of follow-
up [112]. Other reports have found the same pattern; however,
treatment is only effective prior to the development of ESKD
[57, 113, 115]. In another study, Heeringa et al. [57] reported
that up to 50% of children with COQ6 mutations achieved
complete or partial remission with CoQ10 supplementation
with or without an angiotensin-converting enzyme inhibitor
(ACEi). More recently, mutations in the aarF domain-
containing kinase 4 (ADCK4) gene were reported as a cause
of SRNS [116]. ADCK4 interacts with components of the
CoQ10 biosynthesis pathway, and patients with ADCK4 mu-
tations have been reported to have reduced cellular CoQ10
content [116]. In one study, a child with a homozygous frame-
shift mutation in ADCK4 and SRNS was successfully treated
with CoQ10 supplementation [116]. These studies clearly il-
lustrate the power of genomics in the identification of thera-
pies based on the underlying mechanisms of disease.
Vitamin B12
Mutations in the cubilin (CUBN) gene have been reported in
children with intermittent proteinuria [117]. Cubilin is a
coreceptor for the intestinal vitamin B12-intrinsic factor com-
plex, and it is also essential for tubular reabsorption of protein
in the proximal tubule [118]. It is therefore conceivable that
treatment with vitamin B12 may ameliorate proteinuria associ-
ated with CUBN mutation. However, there are no reports in the
literature demonstrating the benefit of vitamin B12 supplemen-
tation in the treatment of proteinuria due to CUBN mutations.
Other agents
In addition to identification of specific molecules that may be
replaced to reverse phenotypes induced by genetic SRNS,
some SRNS-associated genetic mutations have also been
shown to be viable therapeutic targets. For example, mutations
in the transient receptor potential cation channel, subfamily C,
member 6 (TRPC6) can cause autosomal dominant FSGS
through aberrant calcium ion conductance in podocytes
[103, 119]. Therefore, modification of TRPC6 enzymatic ac-
tivity may represent a novel therapeutic approach in the treat-
ment of FSGS. Indeed, there are already published proof-of-
principle data to show that pharmacological targeting of
TRPC6 and other TRPCs is feasible for treating diseases that
are associated with TRPC overactivity [120, 121]. More re-
cently, in a study designed to identify pathways that are
perturbed in FSGS due to mutations in the ANLN gene, we
showed that dysregulation of the PI-3K/AKT/mTOR/Rac1
Pediatr Nephrol
signaling axis and activation of mTOR-driven endoplasmic
reticulum (ER) stress are responsible for the aberrant podocyte
phenotype seen in cell lines overexpressing mutant ANLN
[122]. Furthermore, we identified existing compounds and
novel compounds that may reverse the abnormal podocyte
phenotype, showing that rational therapeutic targets for famil-
ial FSGS can be identified through rigorous biochemical char-
acterization of dysregulated podocyte phenotypes [122].
Supportive therapy
There are multiple publications to show that supportive mea-
sures such as the use of angiotensin receptor blockade to re-
duce proteinuria, aggressive blood pressure control, and the
use of lipid-lowering agents are useful in both non-genetic and
genetic SRNS to slow progression of disease [123, 124].
Kidney transplantation
Monogenic SRNS portends a highly unfavorable long-term
prognosis, as ~ 50% of patients will develop ESKD requiring
dialysis and kidney transplantation within 10 years of diagno-
sis [15]. Fortunately, several studies have shown that the risk
of disease recurrence post-transplantation in patients with ge-
netic SRNS is low compared with those with non-genetic
SRNS [125, 126]. Ding et al. [52] reported a recurrence rate
of 0% (0/25) in genetic SRNS compared with 30% (26/86) in
those with non-genetic SRNS. We reported the same pattern in
a large cohort of North American children with ESKD due to
FSGS who received kidney transplantation over 10 years
[127]. Because the risk of post-transplant recurrence is very
low in genetic SRNS, deceased donor and living-related donor
(LRD) transplant can be planned with great optimism after
excluding the disease-causing mutations in living donors.
Scrupulous planning, however, will be required prior to
embarking on LRD kidney transplantation from family mem-
bers of patients with known single gene defects, regardless of
the mode of inheritance [34]. In autosomal recessive condi-
tions for example, the effect of reducing renal mass by 50%
(i.e., acquired solitary kidney) in a heterozygous carrier is
unknown, and the risk of developing kidney disease in that
setting as a result of modifier genes and/or environmental
factors is also not clear. In autosomal dominant conditions,
family members should not be considered as LRD candidate
until the mutation has been ruled out in the donor because of
variable penetrance associated with AD gene and the exis-
tence of asymptomatic carriers who may develop kidney dis-
ease following reduction of kidney mass by 50%, or the po-
tential of implanting a kidney that may not function optimally
in the recipient [128]. Thus, we do not support the use of LRD
donation from families with known hereditary disease and
Pediatr Nephrol

Fig. 2 Approach to management of a child with non-genetic steroid-resistant nephrotic syndrome (SRNS)

unknown gene defects. If the gene defect is known, LRD
kidneys should only be accepted if the mutation has been ruled
out in the potential donor.
Treatment guidelines for non-genetic
and genetic SRNS
Children with SRNS are often challenging to manage be-
cause many of the agents used are often not effective in
majority of patients. In fact, the single most important
predictor of response to most of these agents is the initial
response to corticosteroid therapy. As described above,
about 60% of patients with SRNS will achieve partial or
complete remission following use of immunomodulatory
agents other than glucocorticoids; however, there are no
robust clinical or laboratory predictors of response to these
agents. Despite this lack of predictors, there are guidelines
for the therapy of non-genetic SRNS based on accumulated
clinical experience and expert opinions; an example is the
Kidney Disease Improving Global Outcomes (KDIGO)
guideline (Fig. 2) [3]. The overall goal of most of these

Fig. 3 Suggested approach to management of a child with genetic steroid-resistant nephrotic syndrome (SRNS)

treatment approaches is to use a combination of immuno-
modulatory and supportive agents to achieve complete or
partial remission in order to delay progression of disease
and development of ESKD. Because overall experience
with treatment of genetic SRNS is limited, there are no
such treatment guidelines for children with genetic
SRNS. As described in previous sections, most cases of
genetic SRNS are due to defective proteins that are impor-
tant for maintaining the functional and structural integrity
of the podocyte and other components of the slit dia-
phragm. It is therefore logical to assume that most of the
immunomodulatory agents will not be effective in the
treatment of genetic SRNS; in fact, most limited small se-
ries support this approach, as over 90% of patients with
genetic SRNS have been reported to be unresponsive to
different immunomodulatory agents. Thus, the approach
of most clinicians is to offer only supportive therapy and
measures to slow progression of CKD in these children.
Importantly, there are pre-clinical data and limited case
series that suggest that immunomodulatory agents may be
beneficial in the treatment of genetic SRNS, as discussed
in the preceding paragraphs. Therefore, we approach the
treatment of children with genetic SRNS in a pragmatic
way by discussing the uncertainty of benefits of therapy
with parents and also by having a low threshold for
discontinuing these therapies to minimize side effects.
Figure 3 shows the approach that we typically use in the
treatment of children with genetic SRNS. There is a need
for randomized trials to evaluate the usefulness of existing
agents in the treatment of genetic SRNS.
Conclusions
Over the past 20 years, advances in genomics have dramat-
ically improved our understanding of the molecular patho-
genesis of NS. Studies have revealed that genetic SRNS
cases make up only a small fraction of SRNS in outbred
populations and that genetic SRNS is heterogeneous.
Diagnosis of genetic SRNS may allow for a more person-
alized approach to therapy and informed discussion of
long-term prognosis and post-kidney transplantation out-
come with families. There are currently no guidelines for
genetic testing in SRNS; however, based on the published
literature, the decision to carry out genetic testing should
be based on the genetic architecture of the disease in the
population where the clinician is practicing. We suggest a
pragmatic approach to the therapy of genetic SRNS, as
there is no evidence-based algorithm for the management
of the disease. There is a need for international collabora-
tive studies to define the genetic architecture of SRNS and
approach to its therapy.
Pediatr Nephrol
Funding The National Institutes of Health (NIH) and National Institute
of Diabetes and Digestive and Kidney Diseases (NIDDK) grants
5R01DK098135 and 5R01DK094987 to RAG, ARB, and AEW are sup-
ported by the Duke Pediatric Research Scholars (DPRS) program.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflicts of
interest.
References
1. Eddy AA, Symons JM (2003) Nephrotic syndrome in childhood.
Lancet 362:629–639
2. McKinney PA, Feltbower RG, Brocklebank JT, Fitzpatrick MM
(2001) Time trends and ethnic patterns of childhood nephrotic
syndrome in Yorkshire, UK. Pediatr Nephrol 16:1040–1044
3. Cattran DC, Feehally J, Cook T, Liu ZH, Fervenza FC, Mezzano
SA, Floege J, Nachman PH, Gipson DS, Praga M, Glassock RJ,
Radhakrishnan J, Hodson EM, Rovin BH, Jha V, Troyanov S, Li
PKT, Wetzels JFM (2012) Kidney disease: improving global out-
comes (KDIGO) glomerulonephritis work group. KDIGO clinical
practice guideline for glomerulonephritis. Kidney Intl Suppl 2:
139–274
4. Ehrich JH, Brodehl J (1993) Long versus standard prednisone
therapy for initial treatment of idiopathic nephrotic syndrome in
children. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Eur J
Pediatr 152:357–361
5. Children ISoKDi (1981) The primary nephrotic syndrome in chil-
dren. Identification of patients with minimal change nephrotic
syndrome from initial response to prednisone. A report of the
International Study of Kidney Disease in Children. J Pediatr 98:
561–564
6. Smith JM, Stablein DM, Munoz R, Hebert D, McDonald RA
(2007) Contributions of the transplant registry: the 2006 annual
report of the North American Pediatric Renal Trials and
Collaborative Studies (NAPRTCS). Pediatr Transplant 11:366–
373
7. Hildebrandt F (2010) Genetic kidney diseases. Lancet 375:1287–
1295
8. Wiggins RC (2007) The spectrum of podocytopathies: a unifying
view of glomerular diseases. Kidney Int 71:1205–1214
9. Sadowski CE, Lovric S, Ashraf S, Pabst WL, Gee HY, Kohl S,
Engelmann S, Vega-Warner V, Fang H, Halbritter J, Somers MJ,
Tan W, Shril S, Fessi I, Lifton RP, Bockenhauer D, El-Desoky S,
Kari JA, Zenker M, Kemper MJ, Mueller D, Fathy HM, Soliman
NA, Group SS, Hildebrandt F (2015) A single-gene cause in
29.5% of cases of steroid-resistant nephrotic syndrome. J Am
Soc Nephrol 26:1279–1289
10. Lovric S, Fang H, Vega-Warner V, Sadowski CE, Gee HY,
Halbritter J, Ashraf S, Saisawat P, Soliman NA, Kari JA, Otto
EA, Hildebrandt F, Nephrotic Syndrome Study Group (2014)
Rapid detection of monogenic causes of childhood-onset ste-
roid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 9:
1109–1116
11. Trautmann A, Bodria M, Ozaltin F, Gheisari A, Melk A, Azocar
M, Anarat A, Caliskan S, Emma F, Gellermann J, Oh J, Baskin E,
Ksiazek J, Remuzzi G, Erdogan O, Akman S, Dusek J, Davitaia T,
Ozkaya O, Papachristou F, Firszt-Adamczyk A, Urasinski T, Testa
S, Krmar RT, Hyla-Klekot L, Pasini A, Ozcakar ZB, Sallay P,
Cakar N, Galanti M, Terzic J, Aoun B, Caldas Afonso A,
Szymanik-Grzelak H, Lipska BS, Schnaidt S, Schaefer F,
PodoNet Consortium (2015) Spectrum of steroid-resistant and
Pediatr Nephrol
congenital nephrotic syndrome in children: the PodoNet registry
cohort. Clin J Am Soc Nephrol 10:592–600
12. Bierzynska A, McCarthy HJ, Soderquest K, Sen ES, Colby E,
Ding WY, Nabhan MM, Kerecuk L, Hegde S, Hughes D, Marks
S, Feather S, Jones C, Webb NJ, Ognjanovic M, Christian M,
Gilbert RD, Sinha MD, Lord GM, Simpson M, Koziell AB,
Welsh GI, Saleem MA (2017) Genomic and clinical profiling of
a national nephrotic syndrome cohort advocates a precision med-
icine approach to disease management. Kidney Int 91:937–947
13. Sampson MG, Gillies CE, Robertson CC, Crawford B, Vega-
Warner V, Otto EA, Kretzler M, Kang HM (2016) Using popula-
tion genetics to interrogate the monogenic nephrotic syndrome
diagnosis in a case cohort. J Am Soc Nephrol 27:1970–1983
14. Buscher AK, Beck BB, Melk A, Hoefele J, Kranz B,
Bamborschke D, Baig S, Lange-Sperandio B, Jungraithmayr T,
Weber LT, Kemper MJ, Tonshoff B, Hoyer PF, Konrad M, Weber
S, German Pediatric Nephrology Association (GPN) (2016)
Rapid response to cyclosporin A and favorable renal outcome in
nongenetic versus genetic steroid-resistant nephrotic syndrome.
Clin J Am Soc Nephrol 11:245–253
15. Trautmann A, Schnaidt S, Lipska-Zietkiewicz BS, Bodria M,
Ozaltin F, Emma F, Anarat A, Melk A, Azocar M, Oh J, Saeed
B, Gheisari A, Caliskan S, Gellermann J, Higuita LMS,
Jankauskiene A, Drozdz D, Mir S, Balat A, Szczepanska M,
Paripovic D, Zurowska A, Bogdanovic R, Yilmaz A, Ranchin
B, Baskin E, Erdogan O, Remuzzi G, Firszt-Adamczyk A,
Kuzma-Mroczkowska E, Litwin M, Murer L, Tkaczyk M,
Jardim H, Wasilewska A, Printza N, Fidan K, Simkova E,
Borzecka H, Staude H, Hees K, Schaefer F, PodoNet
Consortium (2017) Long-term outcome of steroid-resistant ne-
phrotic syndrome in children. J Am Soc Nephrol 28:3055–3065
16. Ding WY, Saleem MA (2012) Current concepts of the podocyte in
nephrotic syndrome. Kidney Res Clin Pract 31:87–93
17. Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S,
Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K,
Reiser J, Mundel P (2008) The actin cytoskeleton of kidney
podocytes is a direct target of the antiproteinuric effect of cyclo-
sporine A. Nat Med 14:931–938
18. Zhao X, Khurana S, Charkraborty S, Tian Y, Sedor JR, Bruggman
LA, Kao HY (2017) Alpha actinin 4 (ACTN4) regulates gluco-
corticoid receptor-mediated transactivation and transrepression in
podocytes. J Biol Chem 292:1637–1647
19. Gbadegesin RA, Hall G, Adeyemo A, Hanke N, Tossidou I,
Burchette J, Wu G, Homstad A, Sparks MA, Gomez J, Jiang R,
Alonso A, Lavin P, Conlon P, Korstanje R, Stander MC, Shamsan
G, Barua M, Spurney R, Singhal PC, Kopp JB, Haller H, Howell
D, Pollak MR, Shaw AS, Schiffer M, Winn MP (2014) Mutations
in the gene that encodes the F-actin binding protein anillin cause
FSGS. J Am Soc Nephrol 25:1991–2002
20. D’Agati VD, Fogo AB, Bruijn JA, Jennette JC (2004) Pathologic
classification of focal segmental glomerulosclerosis: a working
proposal. Am J Kidney Dis 43:368–382
21. D’Agati VD, Kaskel FJ, Falk RJ (2011) Focal segmental
glomerulosclerosis. N Engl J Med 365:2398–2411
22. Fogo AB (2015) Causes and pathogenesis of focal segmental
glomerulosclerosis. Nat Rev Nephrol 11:76–87
23. Buscher AK, Weber S (2012) Educational paper: the
podocytopathies. Eur J Pediatr 171:1151–1160
24. Tryggvason K, Patrakka J, Wartiovaara J (2006) Hereditary pro-
teinuria syndromes and mechanisms of proteinuria. N Engl J Med
354:1387–1401
25. Karp AM, Gbadegesin RA (2017) Genetics of childhood steroid-
sensitive nephrotic syndrome. Pediatr Nephrol 32:1481–1488
26. Shalhoub RJ (1974) Pathogenesis of lipoid nephrosis: a disorder
of T-cell function. Lancet 2:556–560
27. Coward RJ, Foster RR, Patton D, Ni L, Lennon R, Bates DO,
Harper SJ, Mathieson PW, Saleem MA (2005) Nephrotic plasma
alters slit diaphragm-dependent signaling and translocates
nephrin, podocin, and CD2 associated protein in cultured human
podocytes. J Am Soc Nephrol 16:629–637
28. Zimmerman SW (1984) Increased urinary protein excretion in the
rat produced by serum from a patient with recurrent focal glomer-
ular sclerosis after renal transplantation. Clin Nephrol 22:32–38
29. Davin JC (2016) The glomerular permeability factors in idiopathic
nephrotic syndrome. Pediatr Nephrol 31:207–215
30. Weisinger JR, Kempson RL, Eldridge FL, Swenson RS (1974)
The nephrotic syndrome: a complication of massive obesity.
Ann Intern Med 81:440–447
31. Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD
(2001) Obesity-related glomerulopathy: an emerging epidemic.
Kidney Int 59:1498–1509
32. Bhathena DB, Julian BA, McMorrow RG, Baehler RW (1985)
Focal sclerosis of hypertrophied glomeruli in solitary functioning
kidneys of humans. Am J Kidney Dis 5:226–232
33. Schreuder MF, Langemeijer ME, Bokenkamp A, Delemarre-Van
de Waal HA, Van Wijk JA (2008) Hypertension and
microalbuminuria in children with congenital solitary kidneys. J
Paediatr Child Health 44:363–368
34. Gbadegesin RA, Winn MP, Smoyer WE (2013) Genetic testing in
nephrotic syndrome—challenges and opportunities. Nat Rev
Nephrol 9:179–184
35. Bierzynska A, Soderquest K, Koziell A (2014) Genes and
podocytes—new insights into mechanisms of podocytopathy.
Front Endocrinol (Lausanne) 5:226
36. Ebarasi L, Ashraf S, Bierzynska A, Gee HY, McCarthy HJ, Lovric
S, Sadowski CE, Pabst W, Vega-Warner V, Fang H, Koziell A,
Simpson MA, Dursun I, Serdaroglu E, Levy S, Saleem MA,
Hildebrandt F, Majumdar A (2015) Defects of CRB2 cause
steroid-resistant nephrotic syndrome. Am J Hum Genet 96:153–
161
37. Miyake N, Tsukaguchi H, Koshimizu E, Shono A, Matsunaga S,
Shiina M, Mimura Y, Imamura S, Hirose T, Okudela K, Nozu K,
Akioka Y, Hattori M, Yoshikawa N, Kitamura A, Cheong HI,
Kagami S, Yamashita M, Fujita A, Miyatake S, Tsurusaki Y,
Nakashima M, Saitsu H, Ohashi K, Imamoto N, Ryo A, Ogata
K, Iijima K, Matsumoto N (2015) Biallelic mutations in nuclear
pore complex subunit NUP107 cause early-childhood-onset
steroid-resistant nephrotic syndrome. Am J Hum Genet 97:555–
566
38. Braun DA, Sadowski CE, Kohl S, Lovric S, Astrinidis SA, Pabst
WL, Gee HY, Ashraf S, Lawson JA, Shril S, Airik M, Tan W,
Schapiro D, Rao J, Choi WI, Hermle T, Kemper MJ, Pohl M,
Ozaltin F, Konrad M, Bogdanovic R, Buscher R, Helmchen U,
Serdaroglu E, Lifton RP, Antonin W, Hildebrandt F (2016)
Mutations in nuclear pore genes NUP93, NUP205 and XPO5
cause steroid-resistant nephrotic syndrome. Nat Genet 48:457–
465
39. Gee HY, Zhang F, Ashraf S, Kohl S, Sadowski CE, Vega-Warner
V, Zhou W, Lovric S, Fang H, Nettleton M, Zhu JY, Hoefele J,
Weber LT, Podracka L, Boor A, Fehrenbach H, Innis JW,
Washburn J, Levy S, Lifton RP, Otto EA, Han Z, Hildebrandt F
(2015) KANK deficiency leads to podocyte dysfunction and ne-
phrotic syndrome. J Clin Invest 125:2375–2384
40. McCarthy HJ, Bierzynska A, Wherlock M, Ognjanovic M,
Kerecuk L, Hegde S, Feather S, Gilbert RD, Krischock L, Jones
C, Sinha MD, Webb NJ, Christian M, Williams MM, Marks S,
Koziell A, Welsh GI, Saleem MA, RADAR the UK SRNS Study
Group (2013) Simultaneous sequencing of 24 genes associated
with steroid-resistant nephrotic syndrome. Clin J Am Soc
Nephrol 8:637–648

41. Warejko JK, Tan W, Daga A, Schapiro D, Lawson JA, Shril S,
Lovric S, Ashraf S, Rao J, Hermle T, Jobst-Schwan T, Widmeier
E, Majmundar AJ, Schneider R, Gee HY, Schmidt JM, Vivante A,
van der Ven AT, Ityel H, Chen J, Sadowski CE, Kohl S, Pabst WL,
Nakayama M, Somers MJG, Rodig NM, Daouk G, Baum M,
Stein DR, Ferguson MA, Traum AZ, Soliman NA, Kari JA, El
Desoky S, Fathy H, Zenker M, Bakkaloglu SA, Muller D, Noyan
A, Ozaltin F, Cadnapaphornchai MA, Hashmi S, Hopcian J, Kopp
JB, Benador N, Bockenhauer D, Bogdanovic R, Stajic N, Chernin
G, Ettenger R, Fehrenbach H, Kemper M, Munarriz RL, Podracka
L, Buscher R, Serdaroglu E, Tasic V, Mane S, Lifton RP, Braun
DA, Hildebrandt F (2018) Whole exome sequencing of patients
with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol
13:53–62
42. Gbadegesin RA, Lavin PJ, Hall G, Bartkowiak B, Homstad A,
Jiang R, Wu G, Byrd A, Lynn K, Wolfish N, Ottati C, Stevens P,
Howell D, Conlon P, Winn MP (2012) Inverted formin 2 muta-
tions with variable expression in patients with sporadic and hered-
itary focal and segmental glomerulosclerosis. Kidney Int 81:94–
99
43. Brown EJ, Schlondorff JS, Becker DJ, Tsukaguchi H, Tonna SJ,
Uscinski AL, Higgs HN, Henderson JM, Pollak MR (2010)
Mutations in the formin gene INF2 cause focal segmental
glomerulosclerosis. Nat Genet 42:72–76
44. Barua M, Brown EJ, Charoonratana VT, Genovese G, Sun H,
Pollak MR (2013) Mutations in the INF2 gene account for a sig-
nificant proportion of familial but not sporadic focal and segmen-
tal glomerulosclerosis. Kidney Int 83:316–322
45. Boyer O, Benoit G, Gribouval O, Nevo F, Tete MJ, Dantal J,
Gilbert-Dussardier B, Touchard G, Karras A, Presne C, Grunfeld
JP, Legendre C, Joly D, Rieu P, Mohsin N, Hannedouche T, Moal
V, Gubler MC, Broutin I, Mollet G, Antignac C (2011) Mutations
in INF2 are a major cause of autosomal dominant focal segmental
glomerulosclerosis. J Am Soc Nephrol 22:239–245
46. Malone AF, Phelan PJ, Hall G, Cetincelik U, Homstad A, Alonso
AS, Jiang R, Lindsey TB, Wu G, Sparks MA, Smith SR, Webb
NJ, Kalra PA, Adeyemo AA, Shaw AS, Conlon PJ, Jennette JC,
Howell DN, Winn MP, Gbadegesin RA (2014) Rare hereditary
COL4A3/COL4A4 variants may be mistaken for familial focal
segmental glomerulosclerosis. Kidney Int 86:1253–1259
47. Lipska BS, Iatropoulos P, Maranta R, Caridi G, Ozaltin F, Anarat
A, Balat A, Gellermann J, Trautmann A, Erdogan O, Saeed B,
Emre S, Bogdanovic R, Azocar M, Balasz-Chmielewska I, Benetti
E, Caliskan S, Mir S, Melk A, Ertan P, Baskin E, Jardim H,
Davitaia T, Wasilewska A, Drozdz D, Szczepanska M,
Jankauskiene A, Higuita LM, Ardissino G, Ozkaya O, Kuzma-
Mroczkowska E, Soylemezoglu O, Ranchin B, Medynska A,
Tkaczyk M, Peco-Antic A, Akil I, Jarmolinski T, Firszt-
Adamczyk A, Dusek J, Simonetti GD, Gok F, Gheissari A,
Emma F, Krmar RT, Fischbach M, Printza N, Simkova E, Mele
C, Ghiggeri GM, Schaefer F, PodoNet Consortium (2013) Genetic
screening in adolescents with steroid-resistant nephrotic syn-
drome. Kidney Int 84:206–213
48. Hinkes BG, Mucha B, Vlangos CN, Gbadegesin R, Liu J,
Hasselbacher K, Hangan D, Ozaltin F, Zenker M, Hildebrandt F,
Arbeitsgemeinschaft fur Paediatrische Nephrologie Study Group
(2007) Nephrotic syndrome in the first year of life: two thirds of
cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1,
and LAMB2). Pediatrics 119:e907–e919
49. Hinkes B, Vlangos C, Heeringa S, Mucha B, Gbadegesin R, Liu J,
Hasselbacher K, Ozaltin F, Hildebrandt F, APN Study Group
(2008) Specific podocin mutations correlate with age of onset in
steroid-resistant nephrotic syndrome. J Am Soc Nephrol 19:365–
371
50. Gbadegesin R, Hinkes BG, Hoskins BE, Vlangos CN, Heeringa
SF, Liu J, Loirat C, Ozaltin F, Hashmi S, Ulmer F, Cleper R,
Pediatr Nephrol
Ettenger R, Antignac C, Wiggins RC, Zenker M, Hildebrandt F
(2008) Mutations in PLCE1 are a major cause of isolated diffuse
mesangial sclerosis (IDMS). Nephrol Dial Transplant 23:1291–
1297
51. Niaudet P (2004) Podocin and nephrotic syndrome: implications
for the clinician. J Am Soc Nephrol 15:832–834
52. Ding WY, Koziell A, McCarthy HJ, Bierzynska A, Bhagavatula
MK, Dudley JA, Inward CD, Coward RJ, Tizard J, Reid C,
Antignac C, Boyer O, Saleem MA (2014) Initial steroid sensitivity
in children with steroid-resistant nephrotic syndrome predicts
post-transplant recurrence. J Am Soc Nephrol 25:1342–1348
53. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P,
Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK,
Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW,
Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR
(2010) Association of trypanolytic ApoL1 variants with kidney
disease in African Americans. Science 329:841–845
54. Freedman BI, Kopp JB, Langefeld CD, Genovese G, Friedman
DJ, Nelson GW, Winkler CA, Bowden DW, Pollak MR (2010)
The apolipoprotein L1 (APOL1) gene and nondiabetic nephropa-
thy in African Americans. J Am Soc Nephrol 21:1422–1426
55. Okamoto K, Tokunaga K, Doi K, Fujita T, Suzuki H, Katoh T,
Watanabe T, Nishida N, Mabuchi A, Takahashi A, Kubo M,
Maeda S, Nakamura Y, Noiri E (2011) Common variation in
GPC5 is associated with acquired nephrotic syndrome. Nat
Genet 43:459–463
56. Ruf RG, Lichtenberger A, Karle SM, Haas JP, Anacleto FE,
Schultheiss M, Zalewski I, Imm A, Ruf EM, Mucha B, Bagga
A, Neuhaus T, Fuchshuber A, Bakkaloglu A, Hildebrandt F,
Arbeitsgemeinschaft Fur Padiatrische Nephrologie Study Group
(2004) Patients with mutations in NPHS2 (podocin) do not re-
spond to standard steroid treatment of nephrotic syndrome. J
Am Soc Nephrol 15:722–732
57. Heeringa SF, Chernin G, Chaki M, Zhou W, Sloan AJ, Ji Z, Xie
LX, Salviati L, Hurd TW, Vega-Warner V, Killen PD, Raphael Y,
Ashraf S, Ovunc B, Schoeb DS, McLaughlin HM, Airik R,
Vlangos CN, Gbadegesin R, Hinkes B, Saisawat P, Trevisson E,
Doimo M, Casarin A, Pertegato V, Giorgi G, Prokisch H, Rotig A,
Nurnberg G, Becker C, Wang S, Ozaltin F, Topaloglu R,
Bakkaloglu A, Bakkaloglu SA, Muller D, Beissert A, Mir S,
Berdeli A, Varpizen S, Zenker M, Matejas V, Santos-Ocana C,
Navas P, Kusakabe T, Kispert A, Akman S, Soliman NA, Krick
S, Mundel P, Reiser J, Nurnberg P, Clarke CF, Wiggins RC, Faul
C, Hildebrandt F (2011) COQ6 mutations in human patients pro-
duce nephrotic syndrome with sensorineural deafness. J Clin
Invest 121:2013–2024
58. Weber S, Gribouval O, Esquivel EL, Moriniere V, Tete MJ,
Legendre C, Niaudet P, Antignac C (2004) NPHS2 mutation anal-
ysis shows genetic heterogeneity of steroid-resistant nephrotic
syndrome and low post-transplant recurrence. Kidney Int 66:
571–579
59. Gigante M, Greco P, Defazio V, Lucci M, Margaglione M,
Gesualdo L, Iolascon A (2005) Congenital nephrotic syndrome
of Finnish type: detection of new nephrin mutations and prenatal
diagnosis in an Italian family. Prenat Diagn 25:407–410
60. (1981) Primary nephrotic syndrome in children: clinical signifi-
cance of histopathologic variants of minimal change and of diffuse
mesangial hypercellularity. A report of the International Study of
Kidney Disease in Children. Kidney Int 20:765–771
61. Black DA, Rose G, Brewer DB (1970) Controlled trial of predni-
sone in adult patients with the nephrotic syndrome. Br Med J 3:
421–426
62. Rydel JJ, Korbet SM, Borok RZ, Schwartz MM (1995) Focal
segmental glomerular sclerosis in adults: presentation, course,
and response to treatment. Am J Kidney Dis 25:534–542
Pediatr Nephrol
63. Banfi G, Moriggi M, Sabadini E, Fellin G, D’Amico G, Ponticelli
C (1991) The impact of prolonged immunosuppression on the
outcome of idiopathic focal-segmental glomerulosclerosis with
nephrotic syndrome in adults. A collaborative retrospective study.
Clin Nephrol 36:53–59
64. Korbet SM, Schwartz MM, Lewis EJ (1994) Primary focal seg-
mental glomerulosclerosis: clinical course and response to thera-
py. Am J Kidney Dis 23:773–783
65. Xing CY, Saleem MA, Coward RJ, Ni L, Witherden IR,
Mathieson PW (2006) Direct effects of dexamethasone on human
podocytes. Kidney Int 70:1038–1045
66. Ransom RF, Lam NG, Hallett MA, Atkinson SJ, Smoyer WE
(2005) Glucocorticoids protect and enhance recovery of cultured
murine podocytes via actin filament stabilization. Kidney Int 68:
2473–2483
67. Wada T, Pippin JW, Marshall CB, Griffin SV, Shankland SJ
(2005) Dexamethasone prevents podocyte apoptosis induced by
puromycin aminonucleoside: role of p53 and Bcl-2-related family
proteins. J Am Soc Nephrol 16:2615–2625
68. Mallipattu SK, Guo Y, Revelo MP, Roa-Pena L, Miller T, Ling J,
Shankland SJ, Bialkowska AB, Ly V, Estrada C, Jain MK, Lu Y,
Ma’ayan A, Mehrotra A, Yacoub R, Nord EP, Woroniecki RP,
Yang VW, He JC (2017) Kruppel-like factor 15 mediates
glucocorticoid-induced restoration of podocyte differentiation
markers. J Am Soc Nephrol 28:166–184
69. Mallipattu SK, Liu R, Zheng F, Narla G, Ma’ayan A, Dikman S,
Jain MK, Saleem M, D’Agati V, Klotman P, Chuang PY, He JC
(2012) Kruppel-like factor 15 (KLF15) is a key regulator of
podocyte differentiation. J Biol Chem 287:19122–19135
70. Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D,
Nurnberg G, Garg P, Verma R, Chaib H, Hoskins BE, Ashraf S,
Becker C, Hennies HC, Goyal M, Wharram BL, Schachter AD,
Mudumana S, Drummond I, Kerjaschki D, Waldherr R, Dietrich
A, Ozaltin F, Bakkaloglu A, Cleper R, Basel-Vanagaite L, Pohl M,
Griebel M, Tsygin AN, Soylu A, Muller D, Sorli CS, Bunney TD,
Katan M, Liu J, Attanasio M, O’Toole JF, Hasselbacher K, Mucha
B, Otto EA, Airik R, Kispert A, Kelley GG, Smrcka AV,
Gudermann T, Holzman LB, Nurnberg P, Hildebrandt F (2006)
Positional cloning uncovers mutations in PLCE1 responsible for a
nephrotic syndrome variant that may be reversible. Nat Genet 38:
1397–1405
71. Gee HY, Ashraf S, Wan X, Vega-Warner V, Esteve-Rudd J, Lovric
S, Fang H, Hurd TW, Sadowski CE, Allen SJ, Otto EA, Korkmaz
E, Washburn J, Levy S, Williams DS, Bakkaloglu SA,
Zolotnitskaya A, Ozaltin F, Zhou W, Hildebrandt F (2014)
Mutations in EMP2 cause childhood-onset nephrotic syndrome.
Am J Hum Genet 94:884–890
72. Ashraf S, Kudo H, Rao J, Kikuchi A, Widmeier E, Lawson JA,
Tan W, Hermle T, Warejko JK, Shril S, Airik M, Jobst-Schwan T,
Lovric S, Braun DA, Gee HY, Schapiro D, Majmundar AJ,
Sadowski CE, Pabst WL, Daga A, van der Ven AT, Schmidt JM,
Low BC, Gupta AB, Tripathi BK, Wong J, Campbell K, Metcalfe
K, Schanze D, Niihori T, Kaito H, Nozu K, Tsukaguchi H, Tanaka
R, Hamahira K, Kobayashi Y, Takizawa T, Funayama R,
Nakayama K, Aoki Y, Kumagai N, Iijima K, Fehrenbach H,
Kari JA, El Desoky S, Jalalah S, Bogdanovic R, Stajic N,
Zappel H, Rakhmetova A, Wassmer SR, Jungraithmayr T,
Strehlau J, Kumar AS, Bagga A, Soliman NA, Mane SM,
Kaufman L, Lowy DR, Jairajpuri MA, Lifton RP, Pei Y, Zenker
M, Kure S, Hildebrandt F (2018) Mutations in six nephrosis genes
delineate a pathogenic pathway amenable to treatment. Nat
Commun 9:1960
73. Flanagan WM, Corthesy B, Bram RJ, Crabtree GR (1991)
Nuclear association of a T-cell transcription factor blocked by
FK-506 and cyclosporin A. Nature 352:803–807
74. Bram RJ, Hung DT, Martin PK, Schreiber SL, Crabtree GR (1993)
Identification of the immunophilins capable of mediating inhibi-
tion of signal transduction by cyclosporin A and FK506: roles of
calcineurin binding and cellular location. Mol Cell Biol 13:4760–
4769
75. O’Keefe SJ, Tamura J, Kincaid RL, Tocci MJ, O’Neill EA (1992)
FK-506- and CsA-sensitive activation of the interleukin-2 promot-
er by calcineurin. Nature 357:692–694
76. Clipstone NA, Crabtree GR (1992) Identification of calcineurin as
a key signalling enzyme in T-lymphocyte activation. Nature 357:
695–697
77. Gipson DS, Trachtman H, Kaskel FJ, Greene TH, Radeva MK,
Gassman JJ, Moxey-Mims MM, Hogg RJ, Watkins SL, Fine RN,
Hogan SL, Middleton JP, Vehaskari VM, Flynn PA, Powell LM,
Vento SM, McMahan JL, Siegel N, D’Agati VD, Friedman AL
(2011) Clinical trial of focal segmental glomerulosclerosis in chil-
dren and young adults. Kidney Int 80:868–878
78. Li X, Zhang X, Li X, Wang X, Wang S, Ding J (2014)
Cyclosporine A protects podocytes via stabilization of cofilin-1
expression in the unphosphorylated state. Exp Biol Med
(Maywood) 239:922–936
79. Buscher AK, Kranz B, Buscher R, Hildebrandt F, Dworniczak B,
Pennekamp P, Kuwertz-Broking E, Wingen AM, John U, Kemper
M, Monnens L, Hoyer PF, Weber S, Konrad M (2010)
Immunosuppression and renal outcome in congenital and pediatric
steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 5:
2075–2084
80. Giglio S, Provenzano A, Mazzinghi B, Becherucci F, Giunti L,
Sansavini G, Ravaglia F, Roperto RM, Farsetti S, Benetti E,
Rotondi M, Murer L, Lazzeri E, Lasagni L, Materassi M,
Romagnani P (2015) Heterogeneous genetic alterations in sporad-
ic nephrotic syndrome associate with resistance to immunosup-
pression. J Am Soc Nephrol 26:230–236
81. Klaassen I, Ozgoren B, Sadowski CE, Moller K, van Husen M,
Lehnhardt A, Timmermann K, Freudenberg F, Helmchen U, Oh J,
Kemper MJ (2015) Response to cyclosporine in steroid-resistant
nephrotic syndrome: discontinuation is possible. Pediatr Nephrol
30:1477–1483
82. Stefanidis CJ, Querfeld U (2011) The podocyte as a target: cyclo-
sporin A in the management of the nephrotic syndrome caused by
WT1 mutations. Eur J Pediatr 170:1377–1383
83. Gellermann J, Stefanidis CJ, Mitsioni A, Querfeld U (2010)
Successful treatment of steroid-resistant nephrotic syndrome asso-
ciated with WT1 mutations. Pediatr Nephrol 25:1285–1289
84. Wasilewska AM, Kuroczycka-Saniutycz E, Zoch-Zwierz W
(2011) Effect of cyclosporin A on proteinuria in the course of
glomerulopathy associated with WT1 mutations. Eur J Pediatr
170:389–391
85. Megremis S, Mitsioni A, Mitsioni AG, Fylaktou I, Kitsiou-Tzelli
S, Stefanidis CJ, Kanavakis E, Traeger-Synodinos J (2009)
Nucleotide variations in the NPHS2 gene in Greek children with
steroid-resistant nephrotic syndrome. Genet Test Mol Biomarkers
13:249–256
86. Malina M, Cinek O, Janda J, Seeman T (2009) Partial remission
with cyclosporine A in a patient with nephrotic syndrome due to
NPHS2 mutation. Pediatr Nephrol 24:2051–2053
87. Gargah TT, Lakhoua MR (2011) Mycophenolate mofetil in treat-
ment of childhood steroid-resistant nephrotic syndrome. J Nephrol
24:203–207
88. de Mello VR, Rodrigues MT, Mastrocinque TH, Martins SP, de
Andrade OV, Guidoni EB, Scheffer DK, Martini Filho D,
Toporovski J, Benini V (2010) Mycophenolate mofetil in children
with steroid/cyclophosphamide-resistant nephrotic syndrome.
Pediatr Nephrol 25:453–460
89. Ziswiler R, Steinmann-Niggli K, Kappeler A, Daniel C, Marti HP
(1998) Mycophenolic acid: a new approach to the therapy of

experimental mesangial proliferative glomerulonephritis. J Am
Soc Nephrol 9:2055–2066
90. Hauser IA, Renders L, Radeke HH, Sterzel RB, Goppelt-Struebe
M (1999) Mycophenolate mofetil inhibits rat and human
mesangial cell proliferation by guanosine depletion. Nephrol
Dial Transplant 14:58–63
91. Penny MJ, Boyd RA, Hall BM (1998) Mycophenolate mofetil
prevents the induction of active Heymann nephritis: association
with Th2 cytokine inhibition. J Am Soc Nephrol 9:2272–2282
92. Allison AC, Kowalski WJ, Muller CJ, Waters RV, Eugui EM
(1993) Mycophenolic acid and brequinar, inhibitors of purine
and pyrimidine synthesis, block the glycosylation of adhesion
molecules. Transplant Proc 25:67–70
93. Cattran DC, Wang MM, Appel G, Matalon A, Briggs W (2004)
Mycophenolate mofetil in the treatment of focal segmental
glomerulosclerosis. Clin Nephrol 62:405–411
94. Montane B, Abitbol C, Chandar J, Strauss J, Zilleruelo G (2003)
Novel therapy of focal glomerulosclerosis with mycophenolate
and angiotensin blockade. Pediatr Nephrol 18:772–777
95. Salama AD, Pusey CD (2006) Drug insight: rituximab in renal
disease and transplantation. Nat Clin Pract Nephrol 2:221–230
96. Gulati A, Sinha A, Jordan SC, Hari P, Dinda AK, Sharma S,
Srivastava RN, Moudgil A, Bagga A (2010) Efficacy and safety
of treatment with rituximab for difficult steroid-resistant and -
dependent nephrotic syndrome: multicentric report. Clin J Am
Soc Nephrol 5:2207–2212
97. Prytula A, Iijima K, Kamei K, Geary D, Gottlich E, Majeed A,
Taylor M, Marks SD, Tuchman S, Camilla R, Ognjanovic M,
Filler G, Smith G, Tullus K (2010) Rituximab in refractory ne-
phrotic syndrome. Pediatr Nephrol 25:461–468
98. Ito S, Kamei K, Ogura M, Udagawa T, Fujinaga S, Saito M, Sako
M, Iijima K (2013) Survey of rituximab treatment for childhood-
onset refractory nephrotic syndrome. Pediatr Nephrol 28:257–264
99. Bagga A, Sinha A, Moudgil A (2007) Rituximab in patients with
the steroid-resistant nephrotic syndrome. N Engl J Med 356:2751–
2752
100. Magnasco A, Ravani P, Edefonti A, Murer L, Ghio L, Belingheri
M, Benetti E, Murtas C, Messina G, Massella L, Porcellini MG,
Montagna M, Regazzi M, Scolari F, Ghiggeri GM (2012)
Rituximab in children with resistant idiopathic nephrotic syn-
drome. J Am Soc Nephrol 23:1117–1124
101. Kamei K, Okada M, Sato M, Fujimaru T, Ogura M, Nakayama M,
Kaito H, Iijima K, Ito S (2014) Rituximab treatment combined
with methylprednisolone pulse therapy and immunosuppressants
for childhood steroid-resistant nephrotic syndrome. Pediatr
Nephrol 29:1181–1187
102. Fornoni A, Sageshima J, Wei C, Merscher-Gomez S, Aguillon-
Prada R, Jauregui AN, Li J, Mattiazzi A, Ciancio G, Chen L,
Zilleruelo G, Abitbol C, Chandar J, Seeherunvong W, Ricordi C,
Ikehata M, Rastaldi MP, Reiser J, Burke GW 3rd (2011)
Rituximab targets podocytes in recurrent focal segmental
glomerulosclerosis. Sci Transl Med 3:85ra46
103. Hall G, Gbadegesin RA (2015) Translating genetic findings in
hereditary nephrotic syndrome: the missing loops. Am J Physiol
Renal Physiol 309:F24–F28
104. Turunen M, Olsson J, Dallner G (2004) Metabolism and function
of coenzyme Q. Biochim Biophys Acta 1660:171–199
105. Tran UC, Clarke CF (2007) Endogenous synthesis of coenzyme Q
in eukaryotes. Mitochondrion (7 Suppl):S62–S71
106. Crane FL (2007) Discovery of ubiquinone (coenzyme Q) and an
overview of function. Mitochondrion (7 Suppl):S2–S7
107. Bentinger M, Brismar K, Dallner G (2007) The antioxidant role of
coenzyme Q. Mitochondrion (7 Suppl):S41–S50
108. Doimo M, Desbats MA, Cerqua C, Cassina M, Trevisson E,
Salviati L (2014) Genetics of coenzyme q10 deficiency. Mol
Syndromol 5:156–162
Pediatr Nephrol
109. Desbats MA, Vetro A, Limongelli I, Lunardi G, Casarin A, Doimo
M, Spinazzi M, Angelini C, Cenacchi G, Burlina A, Rodriguez
Hernandez MA, Chiandetti L, Clementi M, Trevisson E, Navas P,
Zuffardi O, Salviati L (2015) Primary coenzyme Q10 deficiency
presenting as fatal neonatal multiorgan failure. Eur J Hum Genet
23:1254–1258
110. Payet LA, Leroux M, Willison JC, Kihara A, Pelosi L, Pierrel F
(2016) Mechanistic details of early steps in coenzyme Q biosyn-
thesis pathway in yeast. Cell Chem Biol 23:1241–1250
111. Acosta MJ, Vazquez Fonseca L, Desbats MA, Cerqua C, Zordan
R, Trevisson E, Salviati L (2016) Coenzyme Q biosynthesis in
health and disease. Biochim Biophys Acta 1857:1079–1085
112. Montini G, Malaventura C, Salviati L (2008) Early coenzyme Q10
supplementation in primary coenzyme Q10 deficiency. N Engl J
Med 358:2849–2850
113. Diomedi-Camassei F, Di Giandomenico S, Santorelli FM, Caridi
G, Piemonte F, Montini G, Ghiggeri GM, Murer L, Barisoni L,
Pastore A, Muda AO, Valente ML, Bertini E, Emma F (2007)
COQ2 nephropathy: a newly described inherited
mitochondriopathy with primary renal involvement. J Am Soc
Nephrol 18:2773–2780
114. Ozaltin F (2014) Primary coenzyme Q10 (CoQ 10) deficiencies
and related nephropathies. Pediatr Nephrol 29:961–969
115. Starr MC, Chang IJ, Finn LS, Sun A, Larson AA, Goebel J,
Hanevold C, Thies J, Van Hove JLK, Hingorani SR, Lam C
(2018) COQ2 nephropathy: a treatable cause of nephrotic syn-
drome in children. Pediatr Nephrol. https://doi.org/10.1007/
s00467-018-3937-z
116. Ashraf S, Gee HY, Woerner S, Xie LX, Vega-Warner V, Lovric S,
Fang H, Song X, Cattran DC, Avila-Casado C, Paterson AD,
Nitschke P, Bole-Feysot C, Cochat P, Esteve-Rudd J,
Haberberger B, Allen SJ, Zhou W, Airik R, Otto EA, Barua M,
Al-Hamed MH, Kari JA, Evans J, Bierzynska A, Saleem MA,
Bockenhauer D, Kleta R, El Desoky S, Hacihamdioglu DO, Gok
F, Washburn J, Wiggins RC, Choi M, Lifton RP, Levy S, Han Z,
Salviati L, Prokisch H, Williams DS, Pollak M, Clarke CF, Pei Y,
Antignac C, Hildebrandt F (2013) ADCK4 mutations promote
steroid-resistant nephrotic syndrome through CoQ10 biosynthesis
disruption. J Clin Invest 123:5179–5189
117. Ovunc B, Otto EA, Vega-Warner V, Saisawat P, Ashraf S,
Ramaswami G, Fathy HM, Schoeb D, Chernin G, Lyons RH,
Yilmaz E, Hildebrandt F (2011) Exome sequencing reveals
cubilin mutation as a single-gene cause of proteinuria. J Am Soc
Nephrol 22:1815–1820
118. Amsellem S, Gburek J, Hamard G, Nielsen R, Willnow TE,
Devuyst O, Nexo E, Verroust PJ, Christensen EI, Kozyraki R
(2010) Cubilin is essential for albumin reabsorption in the renal
proximal tubule. J Am Soc Nephrol 21:1859–1867
119. Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T,
Hawkins AF, Daskalakis N, Kwan SY, Ebersviller S, Burchette
JL, Pericak-Vance MA, Howell DN, Vance JM, Rosenberg PB
(2005) A mutation in the TRPC6 cation channel causes familial
focal segmental glomerulosclerosis. Science 308:1801–1804
120. Urban N, Hill K, Wang L, Kuebler WM, Schaefer M (2012) Novel
pharmacological TRPC inhibitors block hypoxia-induced vaso-
constriction. Cell Calcium 51:194–206
121. Zhou Y, Castonguay P, Sidhom EH, Clark AR, Dvela-Levitt M,
Kim S, Sieber J, Wieder N, Jung JY, Andreeva S, Reichardt J,
Dubois F, Hoffmann SC, Basgen JM, Montesinos MS, Weins A,
Johnson AC, Lander ES, Garrett MR, Hopkins CR, Greka A
(2017) A small-molecule inhibitor of TRPC5 ion channels sup-
presses progressive kidney disease in animal models. Science 358:
1332–1336
122. Hall GLB, Khan K, Pediaditakis I, Xiao J, Wu G, Wang L,
Kovalik ME, Chryst-Stangl M, Davis EE, Spurney RF,
Gbadegesin RA (2018) The human FSGS-causing ANLN
Pediatr Nephrol
R431C mutation induces dysregulated PI3K/AKT/mTOR/Rac1
signaling in podocytes. J Am Soc Nephrol 29:2011–2122
123. Bagga A, Mudigoudar BD, Hari P, Vasudev V (2004) Enalapril
dosage in steroid-resistant nephrotic syndrome. Pediatr Nephrol
19:45–50
124. Li Z, Duan C, He J, Wu T, Xun M, Zhang Y, Yin Y (2010)
Mycophenolate mofetil therapy for children with steroid-
resistant nephrotic syndrome. Pediatr Nephrol 25:883–888
125. Wada T, Nangaku M (2015) A circulating permeability factor in
focal segmental glomerulosclerosis: the hunt continues. Clin
Kidney J 8:708–715
126. Konigshausen E, Sellin L (2016) Circulating permeability factors
in primary focal segmental glomerulosclerosis: a review of pro-
posed candidates. Biomed Res Int 2016:3765608
127. Pelletier JHKK, Engen R, Bensimhon A, Varner J, Rheault M,
Srivastava T, Straatmann C, Silva C, Davis TK, Wenderfer S,
Gibson K, Selewski D, Barcia J, Weng P, Licht C, Jawa N,
Kallash M, Foreman JW, Wigfall DR, Chua AN, Chambers E,
Hornik CP, Brewer ED, Nagaraj SK, Greenbaum LA,
Gbadegesin RA (2018) Recurrence of nephrotic syndrome follow-
ing kidney transplantation is associated with initial native kidney
biopsy findings. Pediatr Nephrol 33:1773–1780
128. Winn MP, Alkhunaizi AM, Bennett WM, Garber RL, Howell DN,
B u t t e r l y D W, C o n l o n P J ( 1 9 9 9 ) F o c a l s e g m e n t a l
glomerulosclerosis: a need for caution in live-related renal trans-
plantation. Am J Kidney Dis 33:970–974